The Jansen-de Vries syndrome is caused by truncating mutations the last and penultimate exon of PPM1D. Due to the localization of the mutations at the end of the gene, the mRNA is truncated and not subjected to nonsense mediated mRNA decay (NMD). Whereas it still contains its functional protein phosphatase Mg2+/Mn2+ -dependent (PPM)-type phosphatase domain, it is expected that the nuclear localization signal (NLS) is lost. How the truncating protein leads to intellectual disability and the other associated features, is currently unknown.
PPM1D (Protein phosphatase, Mg2+/Mn2+ dependent 1D), also known as Wip1, encodes a type 2C phosphatase and is, as other PPM/PP2C phosphatases, a regulator of stress response. In particular, PPM1D regulates the DNA Damage response (DDR) pathway by inhibition of p53 and other tumor suppressors. Acquired mutations in PPM1D have been identified in several types of cancers, including breast- and/or ovarian cancer as well as colorectal cancer. However, germline mutations in cancer patients have, to our knowledge, not been reported.
Exposure of patient-derived cells to ionizing radiation resulted in normal p53 activation suggesting that p53 signaling is not affected by the truncated protein. However, a cell growth disadvantage was observed, suggesting a possible effect on the stress response pathway. The underlying pathophysiological mechanism is not yet understood.
PPM1D has previously been shown to be expressed in human and mice brain. It has also been shown that PPM1D is expressed in fetal human tissues. The expression of PPM1D in human fetal brain is suggestive for a role during fetal brain development and, thereby, potentially in developing normal cognition.
Diagnostic testing
Since the Jansen-de Vries syndrome is not highly recognizable, most mutations in PPM1D will be found by whole exome sequencing. But, also direct sequencing of the PPM1D gene by Sanger sequencing can be performed.